Kiyoshi Ohara

Irradiation synchronized with respiration gate

A respiratory gating technique was developed for radiotherapy of tumors unable to remain stable due to respiration. Irradiation was started and stopped with a microwave oscillator of a linear accelerator controlled by gating signals at specific points in the respiratory cycle. This technique was tested in a phantom specially designed to simulate a patient with lung cancer and in clinical therapy for lung tumors of seven patients. A mask was used to check ventilation in the phantom and airbags were used to measure thoracoabdominal pressure in patients and in the phantom; this enabled us to detect the excursion of the tumors. Low sensitivity film for verification demonstrated the efficacy of this technique. The gated irradiation was proved to ensure more precise radiotherapy for tumors located close to the diaphragm.

BENEFITS OF ADJUVANT RADIOTHERAPY AFTER RADICAL RESECTION OF LOCALLY ADVANCED MAIN HEPATIC DUCT CARCINOMA

PURPOSE The objective of this study was to determine the benefits of adjuvant radiotherapy after radical resection of locally advanced main hepatic duct carcinoma (Klatskin tumor). METHODS AND MATERIALS We conducted a retrospective review of 63 patients who underwent surgical resection of Stage IVA Klatskin tumor. Of the 63 patients, 47 had microscopic tumor residue (RT1). Twenty-eight of the 47 patients with RT1 were treated by adjuvant radiotherapy and the remaining 19 patients were treated exclusively by surgical resection. Seventeen of the 28 patients with RT1 were treated by both intraoperative radiotherapy (IORT) and postoperative radiotherapy (PORT); of the remaining 11 patients with RT1, 6 underwent resection and IORT, and 5 underwent resection and PORT. RESULTS The major complication and 30-day operative death rates were significantly lower in the radiation group (9.5% and 0.0%, respectively) than in the resection alone group (28.5% and 9.5%, respectively). Of the eight 5-year survivors with RT1, 6 had adjuvant radiotherapy and the remaining 2 had resection alone. Adjuvant radiotherapy for patients with RT1 yielded significantly (p = 0.0141) higher 5-year survival rates (33.9%) than in the resection alone group (13.5 %). The best 5-year survival rate (39.2 %) was found in patients who underwent a combination of IORT and PORT after resection. The local-regional control rate was significantly higher in the adjuvant radiation group than in the resection alone group (79.2% vs. 31.2%). CONCLUSION Our data clearly suggest the improved prognosis of patients with locally advanced Klatskin tumor by integrated adjuvant radiotherapy with IORT and PORT to complete gross tumor resection with acceptable treatment mortality and morbidity.

Clinical evaluation of proton radiotherapy for non-small-cell lung cancer.

PURPOSE To evaluate the clinical results of proton radiotherapy for patients with non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS Between 1983 and 2000, 51 NSCLC patients were treated with proton beams at the University of Tsukuba. There were 28 patients in Stage I, 9 in Stage II, 8 in Stage III, 1 in Stage IV, and 5 with recurrent disease. Thirty-three patients had squamous cell carcinoma, 17 had adenocarcinoma, and 1 had large-cell carcinoma. Median fraction and total doses given were 3.0 Gy (range 2.0-6.0 Gy), and 76.0 Gy (range 49.0-93.0 Gy), respectively. RESULTS The 5-year overall survival rate was 29% for all patients, 70% for 9 Stage IA patients, and 16% for 19 Stage IB patients, respectively (IA vs. IB: p < 0.05). The 5-year in-field local control rate was higher in patients with Stage IA (89%) when compared with those with Stage IB (39%). Forty-seven patients (92%) experienced acute lung toxicity of Grade 1 or less; 3 had Grade 2, 1 had Grade 3, and none experienced Grade 4 or higher. Patients in the present series showed very little late toxicity. CONCLUSIONS Proton therapy is a very safe and effective treatment for patients with NSCLC, especially for those with early stages. The relative merit of proton therapy in comparison with stereotactic photon radiotherapy or three-dimensional conformal photon radiotherapy remains to be defined through future clinical trials.

Clinical results of fractionated proton therapy

PURPOSE Preliminary results of a multi-site Phase I-II clinical trial investigating the efficacy of high-energy proton beams in a wide variety of human malignancies are reported. METHODS AND MATERIALS Since 1983 proton radiotherapy using 250 MeV proton beams produced by a booster synchrotron of the National Laboratory for High Energy Physics has been carried out at Proton Medical Research Center, University of Tsukuba. As of September 1990, a total of 147 patients received a partial or full treatment with proton beams with curative intent; 92 patients (63%) were treated with proton beams alone and 55 patients (37%) with combined photon and proton beams. There were 91 males and the mean age was 61.8 years old. The follow-up observation period ranged from 10 to 97 months. With regard to a total tumor dose, nearly 80% of patients received 70 Gy or more and 53% received 80 Gy or more. While dose-fractionations used depended upon tumor sites, the large majority of patients received substantially high radiation doses in terms of larger total doses (> 70 Gy) and larger fraction sizes (> 2.5 Gy) than those traditionally used. This fractionation regimen has been used because of limited availability of the accelerator or a shortage of machine time (27-30 weeks/year, 3-3.5 hr/day), and also by the expectation that the superior dose distribution possible with protons will permit administration of high radiation doses without increasing morbidities. In connection with this, we have determined the target volume by setting margins around the tumor boundary as practically small as possible, ranging from 5 to 10 mm. RESULTS AND CONCLUSIONS The current trial has been based on a site and dose searching program, hence a wide variety of tumor sites including the aerodigestive organs has been treated. So far, our judgment is that proton therapy has proven of potential advantage in treatment of the lung, esophageal, liver, uterine cervix, prostate, and head and neck malignancies; and of possible value in treatment of high-grade gliomas, and gastric, urinary bladder, and pediatric tumors.

Proton Beam Therapy for Hepatocellular Carcinoma Adjacent to the Porta Hepatis

PURPOSE To evaluate the efficacy and safety of proton beam therapy (PBT) for patients with hepatocellular carcinoma (HCC) located adjacent to the porta hepatis. METHODS AND MATERIALS Subjects of the study were 53 patients with HCC located within 2 cm of the main portal vein. All patients had tumor confined to the radiation field with no evidence of metastatic disease. All patients had hepatic function levels of a Child-Pugh score of 10 or less, Eastern Cooperative Oncology Group performance status of 2 or less, and no uncontrolled ascites. Patients underwent PBT of 72.6 GyE in 22 fractions from Sept 2001 to Dec 2004. RESULTS After 3 years, the actuarial survival rate was 45.1% and local control rate was 86.0%. Prognostic factors for survival included Child-Pugh score, number of tumors, and alpha-fetoprotein levels. No late treatment-related toxicity of Grade 2 or higher was observed. CONCLUSIONS The PBT delivering 72.6 GyE in 22 fractions appears to be effective and safe for HCC adjacent to the porta hepatis.

Proton beam therapy for hepatocellular carcinoma with limited treatment options

The authors conducted a retrospective review to define the usefulness of proton beam therapy for patients who had hepatocellular carcinoma (HCC) with limited treatment options.

Proton Beam Therapy for Hepatocellular Carcinoma Patients with Severe Cirrhosis

Background and Purpose:Hepatocellular carcinoma (HCC) patients with severe cirrhosis are usually treated with supportive care because of their poor prognosis. However, the survival of severe cirrhotic patients has recently improved due to advanced treatments. The aim of this study was to define the role of proton beam therapy for HCC patients with severe cirrhosis.Patients and Methods:19 HCC patients with Child-Pugh class C cirrhosis received proton beam therapy. The hepatic tumors were solitary in 14 patients and multiple in five, and the tumor size was 25–80 mm (median 40 mm) in maximum diameter. No patient had regional lymph node or distant metastasis. Total doses of 50–84 Gy (median 72 Gy) in ten to 24 fractions (median 16) were delivered to the tumors.Results:Of the 19 patients, six, eight and four died of cancer, liver failure and intercurrent diseases, respectively, during the follow-up period of 3–63 months (median 17 months) after treatment. A remaining patient was alive with no evidence of disease 33 months after treatment. All but one of irradiated tumors were controlled during the follow-up period. Ten patients had new intrahepatic tumors outside the irradiated volume. The overall and progression-free survival rates were 53% and 47% at 1 year, respectively, and 42% each at 2 years. Performance status and Child-Pugh score were significant prognostic factors for survival. Therapy-related toxicity of grade 3 or more was not observed.Conclusion:Proton beam therapy for HCC patients with severe cirrhosis was tolerable. It may improve survival for patients with relatively good general condition and liver function.Hintergrund und Ziel:Patienten mit Leberzellkarzinom (HCC [„hepatocellular carcinoma“]) und schwerer Zirrhose werden aufgrund der schlechten Prognose gewöhnlich konservativ behandelt. Allerdings haben fortschrittliche Therapien in letzter Zeit zu einer Verbesserung der Überlebenszeit von Patienten mit schwerer Zirrhose geführt. Das Ziel der vorliegenden Studie war die Bestimmung der Rolle einer Protonentherapie für HCC-Patienten mit schwerer Zirrhose.Patienten und Methodik:19 HCC-Patienten mit Zirrhose der Child-Pugh-Klasse C wurden mit Protonenstrahlen behandelt. 14 Patienten wiesen einzelne und fünf Patienten multiple Lebertumoren auf. Hinsichtlich der Tumorgröße variierte der maximale Durchmesser dabei zwischen 25 und 80 mm (durchschnittlich 40 mm). Keiner der Patienten hatte regionäre Lymphknoten- oder Fernmetastasen in regionären oder entfernten Lymphknoten. Die Gesamtstrahlendosis betrug 50–84 Gy (durchschnittlich 72 Gy) und wurde in zehn bis 24 Fraktionen (durchschnittlich 16 Fraktionen) verabreicht.Ergebnisse:Im Nachuntersuchungszeitraum von 3–63 Monaten (durchschnittlich 17 Monate) verstarben sechs der insgesamt 19 Patienten an Krebs, acht an Leberversagen und vier an interkurrierenden Erkrankungen. Ein Patient war 33 Monate nach der Behandlung ohne Krankheitszeichen am Leben. Mit einer Ausnahme wurden alle Tumoren während der Nachuntersuchung mit entsprechenden Kontrollen verglichen. Zehn Patienten hatten intrahepatische Tumoren, die außerhalb des bestrahlten Bereichs lagen. Die Gesamt- und die progressionsfreie Überlebensrate betrugen nach 1 Jahr 53% und 47% und nach 2 Jahren 42%. Der Performance-Status und die Child-Pugh-Bewertung waren wichtige prognostische Faktoren für das Überleben.Schlussfolgerung:Die Protonentherapie war für Patienten mit Leberzellkarzinom und schwerer Zirrhose tolerabel. Die Behandlung könnte das Überleben von Patienten mit relativ gutem Allgemeinzustand und guter Leberfunktion verbessern.

Preoperative radiotherapy and surgery for advanced thymoma with invasion to the great vessels

From 1983 to 1994, 12 advanced thymomas with invastion to the great vessels were initially treated by irradiation (mean dose, 18.3 Gy) and subsequent surgical resection. In nine patients, complete resection was possible by concomitant resection of the surrounding tissues, mainly pericardium and/or brachiocephalic vein. Histologically, all tumors showed prominent fibrosis. Ten patients also received postoperative radiotherapy (mean dose, 42.3 Gy). Tumor‐related deaths occurred in only two patients; one who did not receive postoperative irradiation 21 months and one who had viable cells at the surgical margin 10 months after operation. However, there were also 2 patients who died of respiratory failure due to operation and/or irradiation, one 45 days and the other 7 years after the treatment. Preoperative radiotherapy could facilitate complete resection of the advanced thymomas. The prognosis of the patients treated with preoperative radiotherapy seemed fair if followed by adequate resection and subsequent irradiation.

Long-term results of proton beam therapy for carcinoma of the uterine cervix

PURPOSE To determine the role of proton therapy in patients with carcinoma of the uterine cervix. METHODS AND MATERIALS Between 1983 and 1991, 25 patients with squamous cell carcinoma of the uterine cervix (stages IIB-IVA) were treated with a curative intent by external photon irradiation to the pelvis, followed by proton irradiation to the primary tumor, delivering a median total tumor dose of 86 Gy (range 71 Gy/26 Fr-101 Gy/46 Fr), and were followed for a median period of 139 months (range 11-184 months). RESULTS Ten-year overall survival rates for stages IIB and IIIB/IVA patients were 89% and 40%, respectively. Five-year local control rates for stages IIB and IIIB/IVA patients were 100% and 61%, respectively. Four percent of patients experienced severe (Grade 4 or more) late complications in the intestine or urinary bladder at 5 years. CONCLUSION External photon and proton therapy is effective for those who are not eligible for intracavitary irradiation, and who otherwise have a poor prognosis. The results show that tumor control, survival, and morbidity are similar to those after conventional therapy.

Assessment of cervical cancer radioresponse by serum squamous cell carcinoma antigen and magnetic resonance imaging

OBJECTIVE To investigate the possibility of objective clinical assessment of the radioresponse of cervical cancer via determination of serum squamous cell carcinoma antigen levels and magnetic resonance imaging (MRI)‐based estimation of tumor shrinkage. METHODS The cases of 60 patients undergoing definitive radiotherapy for cervical squamous cell carcinoma (stage I–II: n = 20; stage III–IV: n = 40) were reviewed. Measurements of serum squamous cell carcinoma antigen levels (n = 60), estimated tumor volume on preradiotherapy MRIs (n = 60), and evaluated tumor shrinkage on postradiotherapy MRIs available (n = 30) were taken. The relation between postradiotherapy squamous cell carcinoma antigen level 2 months after the start of radiotherapy and disease recurrence was investigated. Regression analysis of tumor volume measured on MRIs was used to estimate the extent of tumor shrinkage 2 months after the start of radiotherapy. RESULTS Preradiotherapy squamous cell carcinoma antigen levels correlated significantly with preradiotherapy tumor volumes. Recurrence was identified in 27 patients as distant (n = 19), distant and local (n = 1), local (n = 5), or regional (n = 2). Of 51 patients with elevated preradiotherapy squamous cell carcinoma antigen levels, 33 achieved normalized levels after radiotherapy. Squamous cell carcinoma antigen normalization was associated with a higher recurrence‐free survival rate at 2 years (74.3%) than that associated with nonnormalization of squamous cell carcinoma antigen (5.6%, P < .001). The extent of shrinkage ranged from 61% to 100%, and there was no local recurrence. CONCLUSION Postradiotherapy squamous cell carcinoma antigen status is a useful indicator of clinical outcome, particularly about tumor recurrence. It is not, however, useful for assessing response to radiotherapy. Magnetic resonance imaging is useful for obtaining an objective assessment of radioresponse.